Methylene Blue-Catalyzed Oxidative Cleavage of N-Carbonylated Indoles

Article abstract of DOI:10.1055/s-0036-1592006

The development of a visible-light-mediated oxidative cleavage of electron-deficient indoles is reported. Methylene blue serves as an effective catalyst and the transformation shows a broad substrate scope. A variety of functional groups are well accommod

Full text of DOI:10.1055/s-0036-1592006

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
©
Georg Thieme Verlag Stuttgart · New York
2018, 50, A–K
special topic
A
en
Synthesis
K. Wu et al.
Special Topic
Methylene Blue-Catalyzed Oxidative Cleavage of N-Carbonylated
Indoles
Kui Wua
Cheng Fangb,c
Sarbjeet Kaura
N
Me
Me
N
S
N
Peng Liu*b
Me
Cl
Me
Ting Wang*a
0
0
0
0
0-
0
0
1
7-
6
3
0
4-
1
4
8
R3
methylene blue (2 mol%)
O
N
electron-deficient indoles
mild conditions
R3
R
a
R1
R2
R1
Department of Chemistry, University at Albany, State
University of New York, 1400 Washington Avenue,
Albany, New York 12222, United States
twang3@albany.edu
air, CF3CH2OH
blue LEDs
N
broad substrates
R
R2
O
computational studies
b
c
Department of Chemistry, University of Pittsburgh,
R = Ac or Boc
219 Parkman Avenue, Pittsburgh, PA 15260, United
18 examples
52–88% yield
States
pengliu@pitt.edu
Computational Modeling & Simulation Program,
University of Pittsburgh, 219 Parkman Avenue,
Pittsburgh, PA 15260, United States
Published as part of the Special Topic Modern Radical
Methods and their Strategic Applications in Synthesis
Received: 27.01.2018
Accepted after revision: 09.04.2018
Published online: 08.05.2018
with such oxidizing agents. Singlet oxygen was then report-
ed to react with N-alkylated indoles to give carbonyl and
amide fragments (Scheme 1, eq 2);4 but such transforma-
tion could not be realized on electron-deficient N-acetylin-
doles, presumably due to their poor nucleophilicities. In-
stead, an ene-type allylic oxidation product was obtained
,6
DOI: 10.1055/s-0036-1592006; Art ID: ss-2018-c0126-st
Abstract The development of a visible-light-mediated oxidative cleav-
age of electron-deficient indoles is reported. Methylene blue serves as
an effective catalyst and the transformation shows a broad substrate
scope. A variety of functional groups are well accommodated in the
mild reaction conditions. The photo-mediated single electron transfer
and oxidative cleavage mechanisms were investigated via density func-
tional theory and Marcus theory calculations.
(
Scheme 1, eq 3).7 More recently, aerobic C–C oxidative
Literature
O
R2
R2
O
Key words methylene blue, visible light, electron-deficient indoles,
Witkop–Winterfeldt oxidation, photocatalysis
strong oxidant
R1
eq 1
NH
N
Pt/O2, O3, CrO3, m-CPBA, NaIO4
H
R1
Oxidative cleavage reaction of aromatic rings is a wide
spread occurrence in nature. Particularly, the oxidative
O
1
transformation of tryptophan to N-formylkynurenine, cata-
R3
eq 2
lyzed by tryptophan 2,3-dioxygenease, is the major oxida-
R3 = Alkyl
N
2
tive and metabolic pathway of tryptophan. It is also the
O
1O2
first key step leading to the biosynthesis of coenzyme NAD.
In 1951, Witkop reported the first chemically oxidative
N
R3
cleavage of the C-2–3 double bond of indoles by catalytic
3
R3 = Ac (EWG)
oxidation (Pt/O ) as well as autoxidation. Different syn-
eq 3
2
OOH
N
R3
thetic procedures were then developed using various re-
agents including peracids, periodic acid, chromic acid, and
4
ozone (Scheme 1, eq 1). Winterfeldt later disclosed a direct
This Work
O
N
procedure to convert Witkop oxidation intermediate to the
Camps cyclization product by using NaH/O and KOt-
2
methylene blue
air, CF3CH2OH
5
Bu/O as oxidant. Since then, the synthetic strategy (Wit-
Ac
eq 4
2
N
kop–Winterfeldt oxidation) has been widely applied in the
synthesis of natural products and pharmaceutical agents.
However, N-substituted indoles are liable to resist oxidation
blue LEDs
O
R
O
R
Scheme 1 Oxidative cleavage of N-carbonylated indoles
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

B
Synthesis
K. Wu et al.
Special Topic
cleavages of N-alkylated indoles were reported by visible
light photocatalysis, where dicyanopyrazine-derived chro-
To test the idea, we started our investigations by screen-
ing different catalysts (catalysts A–D) for the oxidation of
tryptamine derivative 1 (Table 1, entries 1–4). Gladly, it was
found that methylene blue successfully catalyzed the oxida-
tion process in MeOH upon irradiation with blue light-
emitting diodes (LEDs), providing oxidative cleavage prod-
uct 2 in 20% yield (entry 4). Various reaction solvents were
then carefully screened (entries 5–11). We found that the
reaction only proceeded in protic solvents, and more polar
solvent tends to result in better yields (entries 9–11). Tri-
fluroethanol was found to be the optimal solvent, providing
2 in yield of 88% (entry 11). Unfortunately, reactants are de-
composed in the medium of hexafluoroisopropanol (HFIP,
8
2
+
mophore (DPZ) and Ru(bpy)
were used as photocata-
3
9
lysts. Yet, no N-carbonylated substrates were studied in the
reports. Since a major class of protecting group on nitrogen
center is carbonyl-containing groups (Ac, Boc, Cbz, Fmoc,
etc.), we reasoned that new catalytic methods for the oxida-
tive cleavage of such indole substrates under mild condi-
tions might provide a significant synthetic benefit (Scheme
1
, eq 4). Continuing our interest in organic photoredox ca-
10
talysis, herein we report a mild and efficient way to oxi-
dize N-carbonylated indoles via methylene blue-catalyzed
phototransformation.
Table 1 Optimization of Reaction Conditionsa
O
catalyst
solvent
NHBoc
NHBoc
CHO
N
air, blue LEDs
N
Boc
Boc
2
1
Entry
Photocatalyst
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
9
A
B
MeOH
MeOH
MeOH
MeOH
0
0
C
D
D
D
D
D
D
D
D
D
A
B
0
20
0
CH
2
Cl
2
DMF
0
MeCN
MeNO
0
2
0
ClCH
CCl CH
CF
HFIP
2
CH
2
OH
33
47
88
0
10
11
12
13
14
15
1
6c
17
3
2
OH
3
CH
2
OH
CF
CF
CF
CF
CF
3
3
3
3
3
CH
CH
CH
CH
CH
2
2
2
2
2
OH
OH
OH
OH
OH
24
35
0
C
D
–
0
0
Z
Z
Z
N
S
Z
COOH
Me
N
Y
Y
Me
Me
N
N
ClO4
Me
Cl
Me
HO
O
O
X
X
A. 9-Mesityl-10-methyl-
acridinium perchlorate
B. Eosin Y (Y = Br, Z = H)
C. Rose Bengal (Y = I, Z = Cl)
D. Methylene Blue
a
b
c
Reactions irradiated with two 12 W, 450 nm light-emitting diode (LED) flood lamps for 10 h.
Isolated yield.
Reaction conducted in the dark.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

C
Synthesis
K. Wu et al.
Special Topic
entry 12). We then tested other catalysts A–C in trifluro-
ethanol, confirming that the methylene blue provided the
best outcome (entries 13–15). Control experiments verified
that both catalyst and the light irradiation are necessary for
the success of this transformation (entries 16 and 17).
Encouraged by these results, our attention was next fo-
cused on exploring the scope of the photocatalytic oxida-
tion reaction. Table 2 summarizes experiments probing a
variety of substituted indoles. We were pleased to find that
both acetyl (Ac) and tert-butoxycarbonyl (Boc)-protected
indoles could be oxidized under the optimized conditions,
providing the corresponding products in good yields (Table
substituted indole 3e, and C-2,3-disubstituted indole 3f are
well tolerated, providing the corresponding products 4d,e
in good yields of 85%, 68%, and 78%, respectively (entry 1,
d,e). Tryptophan derivative 5 and tryptamine derivative 7
could be oxidized smoothly in excellent yields (entries 2
and 3). Excitingly, a free hydroxyl group was tolerated in
this oxidation reaction (entry 4), demonstrating the mild
nature of the reaction condition. Additionally, a variety of
electron-donating and electron-withdrawing substituents
at C-5 and C-6 positions are accommodated (entries 5–7).
Moreover, oxidizing the cyclic structure frameworks under
the optimized conditions furnished medium-size cyclic
amides in good yields (entries 8 and 9).
2, entry 1, a–c). In addition, C-3 substituted indole 3d, C-2
Table 2 Scope of Oxidative Cleavage of Indolesa
O
R3
R3
R1
methylene blue (2 mol%)
R2
N
R1
N
air, CF3CH2OH
blue LEDs
R2
O
Entry
Indole
Product
Yield (%)b
O
N
R3
R3
R1
R2
N
R1
4a: 68
4b: 84
R2
O
4
c: 75
1
a: R1 = Ac, R2 = R3 = Me
b: R = Ac, R2 = H, R3 = Me
c: R = Boc, R2 = R3 = H
d: R = Boc, R2 = H, R3 = Me
e: R = Boc, R2 = Me, R3 = H
f: R = Boc, R2 = R3 = Me
3
3
3
3
3
3
4d: 85
4e: 68
4f: 78
4
4
4
4
4
4
a: R1 = Ac, R2 = R3 = Me
b: R = Ac, R2 = H, R3 = Me
c: R = Boc, R2 = R3 = H
1
1
1
1
1
d: R = Boc, R = H, R3 = Me
1
2
1
e: R = Boc, R = Me, R3 = H
1
2
1
f: R = Boc, R2 = R3 = Me
1
CO2Me
NHBoc
O
COOMe
2
86
N
N
NHBoc
6
CHO
N
Boc
Boc
Boc
5
O
Ts
N
Boc
3
4
81
74
N
Ts
CHO
Boc
N
Boc
7
8
O
OH
N
N
OH
CHO
Boc
Boc
9
10
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

D
Synthesis
K. Wu et al.
Special Topic
Table 2 (continued)
Entry
Indole
Product
Yield (%)b
O
N
R
R
N
Ac
12a: 72
1
2b: 52
Boc
5
Boc
12c: 86
12d: 70
1
1
1
1
1a: R = 5-F
1
1
1
1
2a: R = 5-F
1b: R = 5-Cl
1c: R = 6-Cl
1d: R = 5-OMe
2b: R = 5-Cl
2c: R = 6-Cl
2d: R = 5-OMe
MeO
MeO
CHO
6
7
CHO
79
74
N
N
Boc
13
14
Boc
O
N
F
F
Boc
N
Cl
Cl
Boc
15
16
O
O
8
70
62
N
N
Boc
17
18
Boc
O
O
9
N
N
O
Boc
Boc
19
20
a
Reactions irradiated with two 12 W, 450 nm LED flood lamps for 10 h at r.t. under air at 1 atm.
Isolated yield.
b
Having demonstrated the high efficiency of the visible-
could be achieved smoothly by treatment of silica gel once
the indole substrates were consumed completely. The in-
dole acetic acid derivatives with different substitutions at
C-5 position are well tolerated, providing 21–23 in good
yields. Amide equivalent 24 and fluoro-substituted aryl am-
ide 25 could also be obtained in good yields of 73% and 85%,
respectively. Under this mild reaction condition, protected
indoleacetic acid 26 could be converted to quinolone 27 in
80% yield, which is the key precursor in the synthesis of Iva-
light-mediated indole oxidation, the applicability of this
chemistry to enable the Witkop–Winterfeldt oxidation to
synthesize 4-quinolone-3-carboxylic acid derivatives was
next investigated. 4-Quinolone-3-carboxylic acid deriva-
tives are privileged structural frameworks in medicinal
11
chemistry. They widely exist in marketed drugs and bio-
logical active agents, such as synthetic antibiotics Cipro-
11
floxacin, Levofloxacin, and Moxifloxacin. Moreover, the
12
14
amide derivative Ivacaftor was recently approved by FDA
for treatment of cystic fibrosis. In addition, this class of
compounds also exhibit a broad array of biological activi-
ties, including antitumor, antiviral, anti-inflammation, anti-
parasitic activities, and activities towards Alzheimer’s dis-
caftor (Scheme 2b,c).
A plausible mechanism for the reaction is outlined in
Scheme 3. Although we could not rule out the possible sin-
glet oxygen involvement during the process,7e our Stern–
Volmer emission quenching experiments (Scheme 3b)
showed that there is redox activity between tryptamine de-
13
ease (Scheme 2a). Given that the 4-quinolone-3-carboxyl-
ate skeleton may represent attractive template for
medicinal evaluation, we were prompted to develop an effi-
cient and mild access to this structure motif. We were
pleased to find that the Witkop–Winterfeldt reaction, oxi-
dative C-2–3 bond cleavage followed by Camps cyclization,
+
rivative 28 and the catalyst methylene blue (M.B. ). There-
fore, we propose that the indole was oxidized via single
electron transfer by methylene blue. The resulting radical
cation 29 was then coupled with a molecule of oxygen to
generate peroxy radical intermediate 30. The peroxy radical
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

E
Synthesis
K. Wu et al.
Special Topic
3
0 could be converted to 31 by accepting an electron from
bon (see Supporting Information), which promotes subse-
quent dioxygen addition to the benzylic radical center. Two
different dioxygen addition transition states to the radical
cation were located. The ‘syn’ isomer (TS1syn), in which the
dioxygen points towards the indole nitrogen, has a 1.8
kcal/mol lower barrier than the ‘anti’ transition state
(TS1anti) in which the dioxygen points away from the indole
nitrogen. The preference for syn-dioxygen addition transi-
tion state is consistent with previous computational studies
on dioxygen addition to π-systems.15 Here, TS1syn and
TS1anti are both computed as doublets, and are only 15.9
reduced methylene blue species, where the photoactive
catalyst (M.B. ) was regenerated. 1,2-Dioxetane formation
+
followed by quick decomposition gave oxidative cleavage
product 33.
We next investigated the proposed mechanism via den-
sity functional theory (DFT) and Marcus theory calcula-
tions. The single electron transfer from 28 to the excited
state M.B. to form 29 and M.B. requires a relatively low
Gibbs free energy barrier of 8.2 kcal/mol. The spin density
of radical cation 29 is mostly localized on the benzylic car-
+
*
·
a
O
N
O
O
N
O
O
N
O
F
F
F
OH
OH
OH
H
N
N
N
OMe
HN
N
O
H
N
H
Ciprofloxacin
Levofloxcin
Moxifloxacin
antibiotics
antibiotics
antibiotics
OH
O
O
O
N
O
O
O
OH
N
H
N
H
N
N
H
OMe
OMe
for treating Alzheimer's disease
Ivacaftor
treatment of cystic fibrosis
selective CB2 agonist
for treating inflammation
BQCA
b
O
O
O
O
O
R1
Methylene Blue
2 mol%)
R1
silica gel
R1
(
R
R
R
CHO
N
N
N
blue LEDs, air, TFE
Boc
Boc
Boc
O
O
O
O
O
N
O
MeO
Br
Me
OEt
OEt
OEt
N
N
Boc
Boc
Boc
21 76%
22 54%
23 84%
F
O
N
O
O
O
N
H
N
H
N
Boc
Boc
24 73%
25 85%
OH
O
c
O
O
methylene blue
(2 mol%)
O
O
OMe
ref.
OMe
N
H
air, CF3CH2OH
blue LEDs
then silica gel
N
N
N
H
Boc
Boc
26
80%
27
Ivacaftor
Scheme 2 Witkop–Winterfeldt indole oxidation
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

F
Synthesis
K. Wu et al.
Special Topic
Scheme 3 Proposed mechanism and mechanistic studies
and 17.8 kcal/mol, respectively, higher in energy compared
to the separate radical cation 29 and a triplet dioxygen. Al-
though our DFT calculations cannot rule out the reaction of
In summary, we have developed a visible-light-mediat-
ed oxidative cleavage of electron-deficient indoles. A broad
range of electron-donating and electron-withdrawing
groups are tolerated on the indole backbone. A variety of
functional groups are well accommodated in the mild reac-
tion conditions. Witkop–Winterfeldt reactions were then
investigated in this photocatalytic system. A reaction mech-
anism was proposed and studied via density functional the-
ory and Marcus theory calculations.
16
29 with singlet dioxygen, the computed barrier to the di-
oxygen addition indicates 29 is reactive enough with the
ground state triplet dioxygen to form peroxy radical 30.
Single electron reduction of 30 to form the zwitterionic
complex 31 is exergonic and facile. Subsequent steps, in-
cluding collapse of 31 to 1,2-dioxetane 32 and decomposi-
tion of 32 to form the final product 33, are both highly exer-
gonic. The mechanism of thermal decomposition of 1,2-di-
oxetane has been well established in the literature,17 and
therefore was not investigated in detail here.
All commercially available chemicals were used without further puri-
fication, unless otherwise noted. Reactions were monitored by TLC
using silica gel 60-F254 plates. TLC plates were visualized by UV fluo-
rescence (254 nm) or stained by Cerium Molybdate followed by heat-
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

G
Synthesis
K. Wu et al.
Special Topic
ing. Purification of the reaction products was carried out by column
chromatography using Siliaflash-P60 (40–63 μm) silica gel available
from Silicycle. 1H-NMR spectra were recorded on a Bruker AV-400
N-(2-Acetylphenyl)-N-formylacetamide (4b)
Following the general procedure 1, compound 3b (35 mg) gave 4b as a
yellow oil; yield: 35 mg (84%).
13
(
400 MHz) and C NMR spectra were recorded on a Bruker AV-400 or
IR (CH Cl ): 1730, 1701, 1367, 1272, 1245, 764 cm–1.
1
2
2
AV-600 (100 MHz or 150 MHz). Data for H NMR are recorded as fol-
1
H NMR (400 MHz, CDCl ): δ = 9.41 (s, 1 H), 7.87 (dd, J = 7.6, 1.4 Hz, 1
lows: chemical shift (δ, ppm), multiplicity (standard abbreviations),
3
13
H), 7.64 (td, J = 7.6, 1.5 Hz, 1 H), 7.57 (td, J = 7.6, 1.2 Hz, 1 H), 7.20 (dd,
J = 7.6, 0.9 Hz, 1 H), 2.55 (s, 3 H), 2.10 (s, 3 H).
coupling constant(s) in hertz (Hz) and integration. Data for C NMR
are reported in terms of chemical shift (δ, ppm). IR spectra were re-
corded on a PerkinElmer Spectrum Two IR spectrometer and only ma-
13
C NMR (100 MHz, CDCl ): δ = 198.73, 172.51, 162.68, 135.81,
3
–1
jor peaks were reported in cm . High-resolution mass spectral analy-
sis (HRMS) data were obtained using Agilent Technologies 6530 Accu-
rate Mass Q-TOF LC/MS. Optical rotations were measured on a
PerkinElmer 351 polarimeter at 589 nm with a 100 mm path length
cell. Irradiation of photochemical reactions was carried out using two
133.58, 133.15, 130.69, 130.07, 129.66, 28.61, 23.98.
+
ESI-HRMS: m/z calcd for C11H11NO Na [M + Na] : 228.0631; found:
3
228.0640.
tert-Butyl Formyl(2-formylphenyl)carbamate (4c)
12W PAR38 blue LED flood lamps from ABi LED lighting. Yields refer
Following the general procedure 1, compound 3c (43 mg) gave 4c as a
reddish oil; yield: 37 mg (75%).
to chromatographically and spectroscopically purified compounds.
The syntheses of all the indoles in Table 2 and Scheme 2 are described
in the Supporting Information.
IR (CH Cl ): 1744, 1699, 1371, 1353, 1291, 1239, 1058, 846, 759, 617
2
2
–1
cm
1H NMR (400 MHz, CDCl
.6, 1.6 Hz, 1 H), 7.69 (td, J = 7.6, 1.6 Hz, 1 H), 7.60 (td, J = 7.6, 0.9 Hz, 1
H), 7.23 (d, J = 7.6 Hz, 1 H), 1.47 (s, 9 H).
.
Photo-Oxidative Cleavage of Indoles; General Procedure 1
3
): δ = 9.97 (s, 1 H), 9.42 (s, 1 H), 7.92 (dd, J =
7
To a 0.1 M solution of indole substrate (0.2 mmol, 1 equiv) in trifluo-
roethanol was added methylene blue (2 mol%) was added. The reac-
tion mixture was irradiated under blue LEDs in the open air for 10 h.
13
C NMR (100 MHz, CDCl ): δ = 189.57, 163.00, 151.66, 134.75,
3
The reaction was quenched with H O and extracted with EtOAc (3 × 5
134.51, 132.93, 132.08, 130.33, 129.35, 84.96, 27.80.
2
mL). The combined organic layers were washed with brine and dried
+
ESI-HRMS: m/z calcd for C13H15NO Na [M + Na] : 272.0893; found:
272.0897.
4
(
Na SO ). After removal of the solvent under reduced pressure, the
2 4
residue was purified on column chromatography to give the corre-
sponding desired product (Table 2).
tert-Butyl (2-Acetylphenyl)(formyl)carbamate (4d)
Following the general procedure 1, compound 3d (46 mg) gave 4d as a
yellowish oil; yield: 44 mg (85%).
tert-Butyl (2-{3-[(tert-Butoxycarbonyl)amino]propanoyl}phe-
nyl)(formyl)carbamate (2)
IR (CH Cl ): 1742, 1692, 1356, 1295, 1251, 1153, 1052, 762 cm–1.
2
2
Following the general procedure 1, compound 1 (72 mg) gave 2 as a
colorless oil; yield: 69 mg (88%).
1H NMR (400 MHz, CDCl
7.58 (t, J = 8.0 Hz, 1 H), 7.50 (t, J = 7.6 Hz, 1 H), 7.18 (d, J = 9.6 Hz, 1 H),
): δ = 9.32 (s, 1 H), 7.85 (d, J = 7.7 Hz, 1 H),
3
IR (CH Cl ): 1743, 1698, 1503, 1368, 1295, 1242, 1154 cm–1.
2
2
2
.54 (s, 3 H), 1.48 (s, 9 H).
1
H NMR (400 MHz, CDCl ): δ = 9.32 (s, 1 H), 7.83 (d, J = 7.6 Hz, 1 H),
3
13
C NMR (100 MHz, CDCl ): δ = 198.12, 163.25, 151.90, 135.04,
3
7
5
.59 (t, J = 7.6 Hz, 1 H), 7.50 (t, J = 7.6 Hz, 1 H), 7.19 (d, J = 7.6 Hz, 1 H),
.06 (s, 1 H), 3.45 (dd, J = 5.8, 5.5 Hz, 2 H), 3.12 (t, J = 5.5 Hz, 2 H), 1.48
132.98, 132.70, 130.66, 129.93, 128.89, 84.42, 28.53, 27.84.
+
(
s, 9 H), 1.42 (s, 9 H).
ESI-HRMS: m/z calcd for C14
H
17NO
4
Na [M + Na] : 286.1050; found:
13
286.1052.
C NMR (100 MHz, CDCl ): δ = 199.88, 163.23, 155.84, 151.90,
3
1
34.52, 132.92, 132.85, 130.76, 129.53, 128.97, 84.54, 79.15, 40.49,
tert-Butyl Acetyl(2-formylphenyl)carbamate (4e)
35.54, 28.34, 27.88.
+
Following the general procedure 1, compound 3e (46 mg) gave 4e as a
white solid; yield: 36 mg (68%); mp 80 °C.
ESI-HRMS: m/z calcd for C20H28N O Na [M + Na] : 415.1840; found:
2
6
415.1842.
IR (CH Cl ): 1743, 1701, 1371, 1255, 1155, 764, 731 cm–1.
2
2
1
N-Acetyl-N-(2-acetylphenyl)acetamide (4a)
H NMR (400 MHz, CDCl ): δ = 9.99 (s, 1 H), 7.88 (dd, J = 7.6, 1.3 Hz, 1
3
Following the general procedure 1, compound 3a (37 mg) gave 4a as a
H), 7.65 (td, J = 7.6, 1.3 Hz, 1 H), 7.54 (t, J = 7.6 Hz, 1 H), 7.17 (d, J = 7.6
yellowish oil; yield: 29 mg (68%).
Hz, 1 H), 2.68 (s, 3 H), 1.34 (s, 9 H).
IR (CH Cl ): 1701, 1368, 1274, 1243, 1019, 747, 598 cm–1.
13C NMR (100 MHz, CDCl
): δ = 189.96, 173.42, 139.32, 134.45,
2
2
3
1
132.44, 132.00, 130.01, 128.56, 83.61, 27.69, 26.36.
H NMR (400 MHz, CDCl ): δ = 7.84 (dd, J = 7.6, 1.6 Hz, 1 H), 7.61 (td,
3
+
J = 7.6, 1.6 Hz, 1 H), 7.57–7.50 (td, J = 7.6, 1.1 Hz, 1 H), 7.19 (dd, J = 7.7,
ESI-HRMS: m/z calcd for C14
H
17NO
4
Na [M + Na] : 286.1050; found:
1.1 Hz, 1 H), 2.55 (s, 3 H), 2.26 (s, 6 H).
286.1050.
13
C NMR (100 MHz, CDCl ): δ = 199.09, 173.05, 137.50, 135.94,
3
tert-Butyl Acetyl(2-acetylphenyl)carbamate (4f)
133.03, 130.66, 129.91, 129.13, 28.71, 26.74.
+
Following the general procedure 1, compound 3f (49 mg) gave 4f as a
colorless oil; yield: 43 mg (78%).
ESI-HRMS: m/z calcd for C12H13NO Na [M + Na] : 242.0788; found:
3
242.0791.
IR (CH Cl ): 1743, 1689, 1371, 1282, 1157, 731 cm–1.
2
2
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

H
Synthesis
K. Wu et al.
Special Topic
1
1
H NMR (400 MHz, CDCl ): δ = 7.80 (d, J = 7.8 Hz, 1 H), 7.52 (t, J = 7.8
H NMR (400 MHz, CDCl ): δ = 7.47 (dd, J = 8.7, 2.9 Hz, 1 H), 7.21(td,
3
3
Hz, 1 H), 7.42 (t, J = 7.8 Hz, 1 H), 7.12 (d, J = 7.8 Hz, 1 H), 2.61 (s, 3 H),
J = 8.8, 2.9 Hz, 1 H), 7.10 (dd, J = 8.7, 5.1 Hz, 1 H), 2.60 (s, 3 H), 2.49 (s,
2
.51 (s, 3 H), 1.34 (s, 9 H).
3 H), 1.35 (s, 9 H).
13
13
C NMR (100 MHz, CDCl ): δ = 198.35, 173.54, 152.15, 137.32,
C NMR (100 MHz, CDCl ): δ = 197.07, 197.05, 173.51, 162.59,
3
3
134.61, 132.59, 130.37, 129.79, 128.07, 83.00, 28.60, 27.71, 26.52;
160.11, 152.01, 136.27, 136.21, 133.16, 133.13, 132.11, 132.03,
+
119.38, 119.16, 116.69, 116.46, 83.31, 28.46, 27.70, 26.43.
ESI-HRMS: m/z calcd for C15H19NO Na [M + Na] : 300.1206; found:
4
+
300.1208.
ESI-HRMS: m/z calcd for C15H18FNO Na [M + Na] : 318.1112; found:
4
318.1113.
Methyl 2-[(tert-Butoxycarbonyl)amino]-4-{2-[N-(tert-butoxycar-
bonyl)formamido]phenyl}-4-oxobutanoate (6)
tert-Butyl Acetyl(2-acetyl-4-chlorophenyl)carbamate (12b)
Following the general procedure 1, compound 5 (83 mg) gave 6 as a
reddish oil; yield: 87 mg (86%); [α]D +97.8 (c 1.5, CHCl3).
Following the general procedure 1, compound 11b (56 mg) gave 12b
as a yellowish oil; yield: 33 mg (52%).
20
IR (CH Cl ): 1744, 1708, 1497, 1368, 1295, 1155, 761 cm–1.
IR (CH Cl ): 1744, 1697, 1371, 1281, 1245, 1156, 1102, 845 cm–1.
2
2
2
2
1
1
H NMR (400 MHz, CDCl ): δ = 9.28 (s, 1 H), 7.82 (s, 1 H), 7.58 (t, J = 7.7
H NMR (400 MHz, CDCl ): δ = 7.75 (d, J = 2.3 Hz, 1 H), 7.50 (dd, J = 8.4,
3
3
Hz, 1 H), 7.48 (t, J = 7.6 Hz, 1 H), 7.17 (d, J = 7.8 Hz, 1 H), 5.44 (s, 1 H),
.60 (s, 1 H), 3.70 (s, 3 H), 3.56 (s, 1 H), 3.41 (d, J = 17.7 Hz, 1 H), 1.46
2.3 Hz, 1 H), 7.07 (d, J = 8.4 Hz, 1 H), 2.61 (s, 3 H), 2.51 (s, 3 H), 1.36 (s,
9 H).
4
(
1
s, 9 H), 1.44 (s, 9 H).
13
C NMR (100 MHz, CDCl ): δ = 197.07, 173.45, 151.83, 136.06,
3
3
C NMR (100 MHz, CDCl ): δ = 198.12, 197.56, 171.77, 171.63,
135.75, 133.84, 132.40, 131.72, 129.72, 83.48, 28.51, 27.73, 26.43.
3
1
1
7
63.12, 162.98, 155.48, 151.78, 151.70, 134.08, 133.40, 133.10,
32.96, 130.92, 130.81, 130.11, 129.58, 129.04, 129.00, 84.56, 84.44,
9.97, 79.89, 52.56, 52.46, 49.42, 42.51, 42.30, 28.24, 27.88, 27.76.
+
+
ESI-HRMS: m/z calcd for C15H18ClNO Na [M + Na] : 334.0817; found:
4
334.0818.
ESI-HRMS: m/z calcd for C22H30N O Na [M + Na] : 473.1894; found:
2
8
tert-Butyl Acetyl(2-acetyl-5-chlorophenyl)carbamate (12c)
473.1897.
Following the general procedure 1, compound 11c (56 mg) gave 12c
as yellow solid; yield: 54 mg (86%); mp 86 °C.
tert-Butyl (2-{3-[N-(tert-Butoxycarbonyl)-4-methylphenylsulfon-
amido]propanoyl}phenyl)(formyl)carbamate (8)
IR (CH Cl ): 1745, 1692, 1371, 1276, 1247, 1156, 1105, 764 cm–1.
2
2
1
H NMR (400 MHz, CDCl ): δ = 7.75 (d, J = 8.4 Hz, 1 H), 7.41 (dd, J = 8.4,
3
Following the general procedure 1, compound 7 (130 mg) gave 8 as a
colorless oil; yield: 111 mg (81%).
2.1 Hz, 1 H), 7.15 (d, J = 2.1 Hz, 1 H), 2.62 (d, J = 8.7 Hz, 3 H), 2.50 (s, 3
H), 1.36 (s, 9 H).
IR (CH Cl ): 1697, 1355, 1289, 1154, 746, 567, 546 cm–1.
2
2
13
C NMR (100 MHz, CDCl ): δ = 197.14, 173.39, 151.67, 138.62,
3
1
H NMR (400 MHz, CDCl ): δ = 9.32 (s, 1 H), 7.90 (dd, J = 8.0, 1.0 Hz, 1
3
138.15, 133.01, 130.82, 130.77, 128.27, 83.56, 28.54, 27.72, 26.45.
H), 7.78 (d, J = 8.0 Hz, 2 H), 7.59 (td, J = 7.7, 1.2 Hz, 1 H), 7.51 (td, J =
.6, 1.2 Hz, 1 H), 7.30 (d, J = 8.0 Hz, 2 H), 7.19 (d, J = 8.0 Hz, 1 H), 4.13
t, J = 7.6 Hz, 2 H), 3.40 (t, J = 7.6 Hz, 2 H), 2.43 (s, 3 H), 1.47 (s, 9 H),
+
ESI-HRMS: m/z calcd for C15H18ClNO Na [M + Na] : 334.0817; found:
4
7
(
334.0817.
1
.35 (s, 9 H).
tert-Butyl Acetyl(2-acetyl-4-methoxyphenyl)carbamate (12d)
13
C NMR (100 MHz, CDCl ): δ = 198.03, 163.14, 151.91, 150.71,
3
Following the general procedure 1, compound 11d (49 mg) gave 12d
as a yellowish oil; yield: 39 mg (70%).
144.30, 137.06, 134.31, 133.08, 132.87, 130.72, 129.58, 129.30,
128.97, 127.72, 84.48, 84.46, 43.01, 40.92, 27.83, 21.55.
): 1738, 1693, 1370, 1281, 1252, 1157, 1042 cm–1
+
IR (CH Cl .
2 2
ESI-HRMS: m/z calcd for C27H34N O SNa [M + Na] : 569.1928; found:
2
8
1
569.1937.
H NMR (400 MHz, CDCl ): δ = 7.29 (d, J = 1.3 Hz, 1 H), 7.03 (d, J = 1.3
3
Hz, 2 H), 3.86 (s, 3 H), 2.60 (s, 3 H), 2.49 (s, 3 H), 1.36 (s, 9 H).
13
tert-Butyl Formyl[2-(3-hydroxypropanoyl)phenyl]carbamate (10)
C NMR (100 MHz, CDCl ): δ = 198.19, 173.73, 158.68, 152.47,
3
Following the general procedure 1, compound 9 (52 mg) gave 10 as a
135.59, 131.20, 129.86, 116.98, 115.74, 82.96, 55.58, 28.56, 27.75,
yellowish oil; yield: 43 mg (74%).
26.56.
IR (CH Cl ): 1744, 1296, 1153, 731 cm–1.
+
ESI-HRMS: m/z calcd for C16
H
21NO
Na [M + Na] : 330.1312; found:
2
2
5
1
330.1316.
H NMR (400 MHz, CDCl ): δ = 9.31 (s, 1 H), 7.83 (dd, J = 7.7, 1.3 Hz, 1
3
H), 7.59 (td, J = 7.7, 1.3 Hz, 1 H), 7.50 (td, J = 7.6, 1.3 Hz, 1 H), 7.20 (dd,
J = 7.8, 0.9 Hz, 1 H), 3.98–3.84 (m, 2 H), 3.12 (t, J = 5.4 Hz, 2 H), 2.41 (s,
tert-Butyl Formyl(2-formyl-4-methoxyphenyl)carbamate (14)
1
H), 1.48 (s, 9 H).
Following the general procedure 1, compound 13 (43 mg) gave 14 was
1
3
obtained as a yellowish oil; yield: 39 mg (79%).
C NMR (100 MHz, CDCl ): δ = 201.09, 163.34, 151.91, 134.79,
3
1
32.90, 132.82, 130.72, 129.48, 128.99, 84.70, 58.19, 42.70, 27.85.
IR (CH Cl ): 1742, 1696, 1500, 1276, 1256, 1152, 748 cm–1.
2
2
+
1
ESI-HRMS: m/z calcd for C15H19NO Na [M + Na] : 316.1155; found:
H NMR (400 MHz, CDCl ): δ = 9.90 (s, 1 H), 9.43 (s, 1 H), 7.41 (d, J =
3
5
316.1155.
2.9 Hz, 1 H), 7.19 (dd, J = 8.6, 2.9 Hz, 1 H), 7.12 (d, J = 8.6 Hz, 1 H), 3.89
(
s, 3 H), 1.47 (s, 9 H).
13
tert-Butyl Acetyl(2-acetyl-4-fluorophenyl)carbamate (12a)
C NMR (100 MHz, CDCl ): δ = 189.12, 163.23, 159.95, 151.98,
3
Following the general procedure 1, compound 11a (52 mg) gave 12a
132.90, 131.25, 127.76, 120.43, 116.20, 84.92, 55.74, 27.83.
as a yellowish oil; yield: 42 mg (72%).
+
ESI-HRMS: m/z calcd for C14H17NO Na [M + Na] : 302.0999; found:
302.1000.
5
IR (CH Cl ): 1743, 1701, 1276, 1254, 1156, 1100, 732, 701 cm–1.
2
2
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

I
Synthesis
K. Wu et al.
Special Topic
tert-Butyl Acetyl(2-acetyl-5-chloro-4-fluorophenyl)carbamate
16)
1-tert-Butyl 3-Ethyl 6-Methyl-4-oxoquinoline-1,3(4H)-dicarboxyl-
ate (21)
(
Following the general procedure 1, compound 15 (59 mg) gave 16 as a
Following the general procedure 2, quinolone 21 was obtained as a
colorless oil; yield: 48 mg (74%).
white solid; yield: 50 mg (76%); mp 190 °C.
IR (CH Cl ): 1747, 1696, 1371, 1281, 1155, 1102, 732 cm–1.
IR (CH Cl ): 1611, 1277, 1234, 1136, 763 cm–1.
2
2
2
2
1
1
H NMR (400 MHz, CDCl ): δ = 7.57 (d, J = 9.0 Hz, 1 H), 7.22 (d, J = 6.6
H NMR (400 MHz, CDCl ): δ = 9.11 (s, 1 H), 8.38 (d, J = 8.9 Hz, 1 H),
3
3
Hz, 1 H), 2.61 (s, 3 H), 2.49 (s, 3 H), 1.38 (s, 9 H).
8.22 (s, 1 H), 7.47 (dd, J = 8.9, 1.8 Hz, 1 H), 4.40 (q, J = 7.1 Hz, 2 H), 2.45
(s, 3 H), 1.69 (s, 9 H), 1.40 (t, J = 7.1 Hz, 3 H).
13
C NMR (100 MHz, CDCl ): δ = 196.02, 196.00, 173.41, 158.22,
3
13
155.71, 151.61, 134.48, 134.43, 133.79, 133.74, 132.68, 125.11,
C NMR (100 MHz, CDCl ): δ = 174.94, 164.81, 149.21, 144.63,
3
124.92, 117.58, 117.35, 83.84, 28.43, 27.73, 26.41.
136.06, 135.35, 134.02, 127.79, 126.80, 119.60, 113.08, 87.66, 61.19,
+
27.83, 20.81, 14.26.
ESI-HRMS: m/z calcd for C15H17ClFNO Na [M + Na] : 352.0722; found:
4
+
352.0724.
ESI-HRMS: m/z calcd for C18H21NO Na [M + Na] : 354.1312; found:
5
354.1304.
tert-Butyl 2,6-Dioxo-3,4,5,6-tetrahydrobenzo[b]azocine-1(2H)-
carboxylate (18)
1-tert-Butyl 3-Ethyl 6-Methoxy-4-oxoquinoline-1,3(4H)-dicarbox-
ylate (22)
Following the general procedure 1, compound 17 (51 mg) gave 8 as a
white solid; yield: 40 mg (70%); mp 88 °C.
Following the general procedure 2, quinolone 22 was obtained as a
IR (CH Cl ): 1772, 1730, 1676, 1243, 1145, 731 cm–1.
yellow solid; yield: 37 mg (54%); mp 310 °C.
2
2
IR (CH Cl .
): 1744, 1682, 1489, 1244, 1137, 1020, 734 cm–1
1
2 2
H NMR (400 MHz, CDCl ): δ = 7.98 (dd, J = 7.8, 1.6 Hz, 1 H), 7.58 (td,
3
1
J = 7.8, 1.6 Hz, 1 H), 7.46 (t, J = 7.6 Hz, 1 H), 7.27 (d, J = 7.6 Hz, 1 H),
.95 (t, J = 8.0 Hz, 2 H), 2.47 (t, J = 7.3 Hz, 2 H), 2.09–1.96 (m, 2 H), 1.37
H NMR (400 MHz, CDCl ): δ = 9.12 (s, 1 H), 8.45 (d, J = 9.5 Hz, 1 H),
3
2
7.86 (d, J = 3.1 Hz, 1 H), 7.25 (dd, J = 9.5, 3.1 Hz, 1 H), 4.41 (q, J = 7.1 Hz,
(s, 9 H).
2 H), 3.91 (s, 3 H), 1.70 (s, 9 H), 1.42 (t, J = 7.1 Hz, 3 H).
13
13
C NMR (100 MHz, CDCl ): δ = 199.38, 172.29, 150.48, 138.67,
C NMR (100 MHz, CDCl ): δ = 174.54, 164.95, 157.45, 149.17,
3
3
136.45, 133.41, 130.73, 129.75, 128.86, 84.03, 40.73, 33.89, 27.69,
144.22, 131.59, 129.47, 122.35, 121.49, 112.49, 107.04, 87.75, 61.22,
21.12.
55.66, 27.82, 14.26.
+
+
ESI-HRMS: m/z calcd for C16H19NO Na [M + Na] : 312.1206; found:
ESI-HRMS: m/z calcd for C18H21NO Na [M + Na] : 370.1261; found:
4
6
312.1205.
370.1254.
tert-Butyl 2,7-Dioxo-2,3,4,5,6,7-hexahydro-1H-benzo[b]azonine-
-carboxylate (20)
1-tert-Butyl 3-Ethyl 6-Bromo-4-oxoquinoline-1,3(4H)-dicarboxyl-
ate (23)
1
Following the general procedure 1, compound 19 (54 mg) gave 20 was
Following the general procedure 2, quinolone 23 was obtained as a
obtained as a white solid; yield: 38 mg (62%); mp 135 °C.
yellow solid; yield: 66 mg (84%); mp 341 °C.
IR (CH Cl ): 1732, 1698, 1451, 1288, 1152, 1115 cm–1.
IR (CH Cl ): 1682, 1421, 1264, 1137, 733 cm–1.
2
2
2
2
1
1
H NMR (400 MHz, CDCl ): δ = 7.51 (td, J = 7.6, 1.0 Hz, 1 H), 7.47 (dd,
H NMR (400 MHz, CDCl ): δ = 9.14 (s, 1 H), 8.55 (d, J = 2.3 Hz, 1 H),
3
3
J = 7.6, 1.0 Hz, 1 H) 7.39 (td, J = 7.6, 1.0 Hz, 1 H), 7.23 (d, J = 7.6 Hz, 1
H), 3.26 (s, 1 H), 2.76 (d, J = 4.8 Hz, 2 H), 2.46 (s, 1 H), 2.08 (s, 1 H), 1.90
8.44 (d, J = 9.3 Hz, 1 H), 7.75 (dd, J = 9.3, 2.4 Hz, 1 H), 4.41 (q, J = 7.1 Hz,
2 H), 1.70 (s, 9 H), 1.41 (t, J = 7.1 Hz, 3 H).
(
1
d, J = 5.7 Hz, 3 H), 1.46 (s, 9 H).
13
C NMR (100 MHz, CDCl ): δ = 173.50, 164.35, 148.81, 145.01,
3
3
C NMR (100 MHz, CDCl ): δ = 205.32, 177.82, 151.85, 139.26,
136.32, 135.75, 129.85, 129.39, 121.79, 120.15, 113.52, 88.40, 61.42,
3
136.88, 131.43, 129.07, 128.25, 128.02, 83.97, 41.50, 38.51, 27.84,
27.81, 14.24.
2
6.26, 24.55.
+
ESI-HRMS: m/z calcd for C17H18BrNO Na [M + Na] : 418.0261; found:
418.0254.
5
+
ESI-HRMS: m/z calcd for C17H21NO Na [M + Na] : 326.1363; found:
4
326.1361.
tert-Butyl 4-Oxo-3-(phenylcarbamoyl)quinoline-1(4H)-carboxyl-
4-Quinolone-3-carboxylic Acid Derivatives; General Procedure 2
ate (24)
(
Scheme 2)
Following the general procedure 2, compound 24 was obtained as a
yellowish oil; yield: 53 mg (73%).
To a 0.1 M solution of indole-3-acetic acid derivative (0.2 mmol, 1
equiv) in trifluoroethanol was added methylene blue (2 mol%). The
reaction mixture was irradiated with blue LEDs in the open air for 36
h. The mixture was filtered and the filter cake was rinsed with EtOAc.
The filtrate was treated with 10 equiv of silica gel and the mixture
was stirred overnight. After removal of the solvent under reduced
pressure, the residue was purified by column chromatography to give
the corresponding desired 4-quinolone-3-carboxylic acid derivative.
IR (CH Cl ): 1766, 1681, 1605, 1552, 1473, 1279, 1232, 1136, 663 cm–1.
2
2
1
H NMR (400 MHz, CDCl ): δ = 11.88 (s, 1 H), 9.52 (s, 1 H), 8.61 (d, J =
3
8
8
.8 Hz, 1 H), 8.52 (d, J = 8.1 Hz, 1 H), 7.77 (t, J = 8.7 Hz, 3 H), 7.56 (t, J =
.4 Hz, 1 H), 7.37 (t, J = 7.8 Hz, 2 H), 7.14 (t, J = 7.1 Hz, 1 H), 1.74 (s, 9
H).
13C NMR (100 MHz, CDCl
): δ = 178.08, 161.71, 144.95, 137.85,
3
1
2
33.49, 128.91, 126.82, 126.21, 124.13, 120.46, 119.86, 113.14, 88.37,
7.81.
+
ESI-HRMS: m/z calcd for C21H20N O Na [M + Na] : 387.1315; found:
2
44
387.1312.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

J
Synthesis
K. Wu et al.
Special Topic
tert-Butyl 3-[(4-Fluorophenyl)carbamoyl]-4-oxoquinoline-1(4H)-
carboxylate (25)
(6) (a) Liu, S.; Scotti, J. S.; Kozmin, S. A. J. Org. Chem. 2013, 78, 8645.
(b) Lu, Z.; Yang, M.; Chen, P.; Xiong, X.; Li, A. Angew. Chem. Int.
Ed. 2014, 53, 13840. (c) Vasudevan, N.; Kashinath, K.; Reddy, D.
S. Org. Lett. 2014, 16, 6148. (d) Lam, H. Y.; Zhang, Y.; Liu, H.; Xu,
J.; Wong, C. T.; Xu, C.; Li, X. J. Am. Chem. Soc. 2013, 135, 6272.
Following the general procedure 2, compound 25 was obtained as a
yellowish solid; yield: 32 mg (85%); mp 360 °C.
IR (CH Cl ): 1760, 1662, 1621, 1525, 1481, 1280, 1199, 1121 cm–1.
2
2
(e) Yang, Y.; Bai, Y.; Sun, S.; Dai, M. Org. Lett. 2014, 16, 6216.
1
H NMR (400 MHz, CDCl ): δ = 9.49 (s, 1 H), 8.59 (d, J = 8.8 Hz, 1 H),
3
(f) Vasudevan, N.; Jachak, G. R.; Reddy, D. S. Eur. J. Org. Chem.
8.49 (dd, J = 8.0, 1.2 Hz, 1 H), 7.74 (ddd, J = 9.0, 7.8, 3.2 Hz, 3 H), 7.54
2015, 7433. (g) Zhang, X.; Sui, Z.; Jiang, W. J. Org. Chem. 2003,
(t, J = 7.5 Hz, 1 H), 7.05 (t, J = 8.7 Hz, 2 H), 1.73 (s, 9 H).
68, 4523. (h) Pin, F.; Comesse, S.; Daich, A. Tetrahedron 2011, 67,
13
C NMR (100 MHz, CDCl ): δ = 178.05, 161.67, 160.45, 158.04,
5564. (i) Shankaraiah, N.; Santos, L. S. Tetrahedron Lett. 2009, 50,
520.
3
149.05, 144.91, 137.83, 134.39, 134.36, 133.52, 126.82, 126.78,
1
26.23, 122.03, 121.95, 119.86, 115.61, 115.39, 112.92, 88.43, 27.80.
(7) (a) Schaap, A. P.; Zaklika, K. A. In Singlet Oxygen; Wasserman, H.
H.; Murray, R. W., Eds.; Academic Press: New York, 1979, 174–
+
ESI-HRMS: m/z calcd for C21H19FN O Na [M + Na] : 405.1221; found:
2
4
243. (b) Sundberg, R. J. Chemistry of Indoles; Academic Press:
405.1220.
New York, 1970. (c) Saito, I.; Imuta, M.; Mataugo, S.; Yamamoto,
H.; Matauura, T. Synthesis 1976, 265. (d) Zhang, X.; Foote, C. S.;
Khan, S. I. J. Org. Chem. 1993, 58, 47. (e) Zhang, X.; Foote, C. S.
J. Org. Chem. 1993, 58, 5524.
1
-tert-Butyl 3-Methyl 4-oxoquinoline-1,3(4H)-dicarboxylate (27)
Following the general procedure 2, quinolone 27 was obtained as a
white solid; yield: 48 mg (80%); mp 154 °C.
IR (CH Cl ): 1646, 1611, 1470, 1278, 1262, 1137, 732 cm–1.
(
8) For recent reviews, see: (a) Prier, C. K.; Rankic, D. A.; MacMillan,
D. W. C. Chem. Rev. 2013, 113, 5322. (b) Hopkinson, M. N.;
Sahoo, B.; Li, J. L.; Glorius, F. Chem. Eur. J. 2014, 20, 3874.
2
2
1
H NMR (400 MHz, CDCl ): δ = 9.15 (s, 1 H), 8.48 (d, J = 8.8 Hz, 1 H),
3
(c) Kärkäs, M. D.; Porco, J. A. Jr.; Stephenson, C. R. J. Chem. Rev.
8.45 (dd, J = 8.0, 1.6 Hz, 1 H), 7.72–7.64 (m, 1 H), 7.46 (t, J = 11.5 Hz, 1
2
2
016, 116, 9683. (d) Xuan, J.; Xiao, W.-J. Angew. Chem. Int. Ed.
012, 51, 6828. (e) Yoon, T. P. ACS Catal. 2013, 3, 895.
H), 3.95 (s, 3 H), 1.70 (s, 9 H).
13
C NMR (100 MHz, CDCl ): δ = 174.79, 165.45, 149.13, 145.22,
3
(f) Nicewicz, D. A.; Nguyen, T. M. ACS Catal. 2014, 4, 355.
g) Fukuzumi, S.; Ohkubo, K. Org. Biomol. Chem. 2014, 12, 6059.
h) Hari, D. P.; König, B. Chem. Commun. 2014, 50, 6688.
137.43, 132.86, 127.94, 127.32, 126.05, 119.70, 112.97, 87.98, 52.38,
(
(
27.82.
+
ESI-HRMS: m/z calcd for C16H17NO Na [M + Na] : 326.0999; found:
(i) Romero, N. A.; Nicewicz, D. A. Chem. Rev. 2016, 116, 10075.
(j) Chen, J.-R.; Hu, X.-Q.; Lu, L.-Q.; Xiao, W.-J. Chem. Soc. Rev.
5
326.0998.
2
016, 45, 2044.
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016, 6, 6853. (b) Ji, X.; Li, D.; Wang, Z.; Tan, M.; Huang, H.;
Deng, G. Eur. J. Org. Chem. 2017, 6652.
(
2
Funding Information
T.W. is grateful to the University at Albany, State University of New
York, for financial support. P. L. thanks the National Science Founda-
(10) (a) Zhao, G.; Kaur, S.; Wang, T. Org. Lett. 2017, 19, 3291. (b) Wu,
K.; Du, Y.; Wang, T. Org. Lett. 2017, 19, 5669.
tion (CHE-1654122) for financial support.
N
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l
Secince
F
o
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n
d
oaitn
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H
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6
5
4
1
2
2)
(11) (a) Mitscher, L. A. Chem. Rev. 2005, 105, 559. (b) Bisacchi, G. S.
J. Med. Chem. 2015, 58, 4874. (c) Huse, H.; Whiteley, M. Chem.
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Acknowledgment
(12) Davis, P. B.; Yasothan, U.; Kirkpatrick, P. Nat. Rev. Drug Discov.
2
012, 11, 349.
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b) Abe, H.; Kawada, M.; Inoue, H.; Ohba, S.; Nomoto, A.;
We thank Dr. Rong Wang (Memorial Sloan-Kettering Cancer Center)
for MASS assistance.
(
(
Watanabe, T.; Shibasaki, M. Org. Lett. 2013, 15, 2124. (c) Jadulco,
R. C.; Pond, C. D.; Van Wagoner, R. M.; Koch, M.; Gideon, O. G.;
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Supporting Information
1
83. (d) Baraldi, P. G.; Saponaro, G.; Moorman, A. R.; Romagnoli,
Supporting information for this article is available online at
R.; Preti, D.; Baraldi, S.; Ruggiero, E.; Varani, K.; Targa, M.;
Vincenzi, F.; Borea, P. A.; Tabrizi, M. A. J. Med. Chem. 2012, 55,
https://doi.org/10.1055/s-0036-1592006.
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
ortioIgnfrm oaitn
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